Neuropeptide Y (hereinafter referred to as NPY) is a peptide composed of 36 amino acid residues and was first isolated from porcine brain by Tatemoto et al. [Nature, vol. 296, 659 (1982)]. NPY is widely distributed in the central nervous system and the peripheral nervous system and regulates various functions in vivo as one of the most abundant peptides in the nervous systems. Namely, NPY functions as an orexigenic substance in the brain and is also related to control of emotion or a function of a central autonomic nervous system. Further, at the periphery, NPY coexists with norepinephrine at the symphathetic nerve terminal and is related to tonicity of the symphathetic nervous system. It is known that the peripheral administration of NPY results in vasoconstriction and increases the effect of other vasopressor substances including norepinephrine.
The functions of NPY are produced by its binding to NPY receptors present in the central or peripheral nervous system. Accordingly, it is possible to prevent the action of NPY by inhibiting the binding of NPY and its receptors. Consequently, substances that antagonize the binding of NPY to its receptors, are expected to be useful for prevention or treatment of various diseases associated with NPY, for example, diseases in the circulatory system, such as hypertension, renal diseases, cardiac diseases or vasospasm, central diseases, such as hyperphagia, depression, epilepsy or dementia, metabolic diseases, such as obesity, diabetes or hormone unbalance, or glaucoma [Trends in Pharmacological Sciences, vol. 15, 153 (1994)].
European Patent No. 355794, Danish Patent No. 3811193 and J. Med. Chem., vol. 37, 811 (1994), etc. disclose that some related derivatives of NPY bind to NPY receptors to antagonize the activity of NPY. In addition, recently, it appeared that certain peptides inhibit the binding of NPY to its receptors (see International Publication WO94/00486 or JP-A-6-116284).
However, these peptidic compounds have substantial problems when they are developed as pharmaceuticals. Namely, such high molecular weight peptides are generally unstable and short-lasting in vivo. Further, these compounds belong to a group of compounds whereby no substantial oral absorption or brain penetration can usually be expected.
On the other hand, recently, it appeared that certain non-peptide compounds inhibit the binding of NPY to NPY receptors and thus antagonize the activities of NPY (see JP-A-6-293794 or German Patent DE4301452-A1).
However, these non-peptide NPY antagonists are structurally totally different from the compounds of the present invention and suggest nothing about the present invention.